The recently identified GABA rho1 receptor allows the GABA receptor structure/function examination, since it expresses well as a homo- oligomer. This receptor is insensitive to bicuculline, baclofen and modulators of GABA-A receptor, and desensitizes very slowly facilitating characterization of this receptor's binding site for agonists and competitive antagonists. The agonist profile of the GABA rho1 is strikingly different from that of the typical GABA-A receptor. Cyclic agonists such as THIP and isonipecotic acid, which are active at GABA-A receptors, are inactive at GABA rho1 receptors. CAMP, a full agonist at GABA rho1, is inert at GABA-A. GABA rho1 may recognize a different conformation of GABA from that recognized by GABA-A receptors. Some agonists at GABA-A, TAMP and imidazole-4-acetic acid, give only small maximum currents and behave as potent competitive antagonists at GABA rho1. The Hill coefficient, close to 2, shows this receptor to be more highly cooperative than GABA-A receptors. The GABA rho1 receptor also requires a different agonist pharmacophore. Muscimol is a potent agonist at both receptor types, but when cyclized as THIP it retains activity only at GABA-A receptors as do isoguvacine and piperidine-4sulfonic acid. The GABA rho1 receptor requires a more extended conformation of GABA. Several endogenously-synthesized neurosteroids, including dehydroepiandro-sterone sulfate, (DHEAS), a potent, noncompetitive antagonist whose actions are independent of the mechanisms of desensitization, modulate GABA responses. DHEAS studies confirm that DHEAS does not block the open ion channel, while decreases in burst duration suggest that DHEAS binds readily to that state of the receptor occupied by GABA but not yet conducting chloride.